Deep Phospho- and Phosphotyrosine Proteomics Identified Active Kinases and Phosphorylation Networks in Colorectal Cancer Cell Lines Resistant to Cetuximab.
Deep Phospho- and Phosphotyrosine Proteomics Identified Active Kinases and Phosphorylation Networks in Colorectal Cancer Cell Lines Resistant to Cetuximab.
复制标题
DOI：
10.1038/s41598-017-10478-9
复制
发表时间：
2017-09-05
影响因子：
4.6
通讯作者：
Tomonaga T
中科院分区：
文献类型：
--
作者：
Abe Y;Nagano M;Kuga T;Tada A;Isoyama J;Adachi J;Tomonaga T
细胞磷酸化异常与肿瘤发生密切相关。因此，激酶抑制剂，特别是酪氨酸激酶抑制剂（TKI），已被开发为抗癌药物。基因组分析已用于TKI敏感性的研究，但某些类型的TKI耐药性无法通过基因组数据进行分类。因此，整体蛋白质组学分析，特别是磷酸酪氨酸（pY）蛋白质组学分析，可以有助于预测TKI敏感性和克服TKI耐药癌症。在这项研究中，我们进行了深度磷酸化蛋白质组学分析，以选择对西妥昔单抗具有内在耐药性的结直肠癌中的活性激酶候选物。通过进行基于固定化金属离子亲和色谱的磷酸化蛋白质组学和高灵敏度pY蛋白质组学分析获得深度磷酸化蛋白质组学数据。敏感（LIM 1215和DLD 1）和耐药细胞系（HCT 116和HT 29）之间的比较揭示了后者中的活性激酶候选物，其中大部分通过pY蛋白质组学分析鉴定。值得注意的是，在大多数这些激酶中没有分配基因组突变。对活性激酶候选物的基于磷酸化的信号网络分析表明，SRC-PRKCD级联在HCT 116细胞中被组成性激活。用SRC抑制剂处理显著抑制HCT 116细胞的增殖。总之，我们基于深度磷酸化蛋白质组学数据的结果使我们提出了针对西妥昔单抗耐药的新的治疗靶点，并显示了抗癌治疗的潜力。
Abnormality in cellular phosphorylation is closely related to oncogenesis. Thus, kinase inhibitors, especially tyrosine kinase inhibitors (TKIs), have been developed as anti-cancer drugs. Genomic analyses have been used in research on TKI sensitivity, but some types of TKI resistance have been unclassifiable by genomic data. Therefore, global proteomic analysis, especially phosphotyrosine (pY) proteomic analysis, could contribute to predict TKI sensitivity and overcome TKI-resistant cancer. In this study, we conducted deep phosphoproteomic analysis to select active kinase candidates in colorectal cancer intrinsically resistant to Cetuximab. The deep phosphoproteomic data were obtained by performing immobilized metal-ion affinity chromatography-based phosphoproteomic and highly sensitive pY proteomic analyses. Comparison between sensitive (LIM1215 and DLD1) and resistant cell lines (HCT116 and HT29) revealed active kinase candidates in the latter, most of which were identified by pY proteomic analysis. Remarkably, genomic mutations were not assigned in most of these kinases. Phosphorylation-based signaling network analysis of the active kinase candidates indicated that SRC-PRKCD cascade was constitutively activated in HCT116 cells. Treatment with an SRC inhibitor significantly inhibited proliferation of HCT116 cells. In summary, our results based on deep phosphoproteomic data led us to propose novel therapeutic targets against cetuximab resistance and showed the potential for anti-cancer therapy.
登录
查看更多内容
影响因子：
8.8
作者：
Marzi, L.;Combes, E.;Vie, N.;Ayrolles-Torro, A.;Tosi, D.;Desigaud, D.;Perez-Gracia, E.;Larbouret, C.;Montagut, C.;Iglesias, M.;Jarlier, M.;Denis, V.;Linares, L. K.;Lam, E. W-F;Martineau, P.;Del Rio, M.;Gongora, C.
通讯作者：
Gongora, C.
影响因子：
4.8
作者：
Khan, Elaine M.;Heidinger, Jill M.;Goldkorn, Tzipora
通讯作者：
Goldkorn, Tzipora
影响因子：
14.9
作者：
UniProt Consortium
通讯作者：
UniProt Consortium
影响因子：
14.9
作者：
Hornbeck PV;Zhang B;Murray B;Kornhauser JM;Latham V;Skrzypek E
通讯作者：
Skrzypek E
影响因子：
3.4
作者：
Matsumoto, Masaki;Oyamada, Koji;Nakayama, Keiichi I.
通讯作者：
Nakayama, Keiichi I.